Molecular Mechanisms of Obesity in Children Exposed to Phthalates in Utero

子宫内接触邻苯二甲酸盐的儿童肥胖的分子机制

• 批准号: 8496565
• 负责人: Nina T Holland
• 金额: $ 63.29万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496565
• 关键词: 14 year old; 9 year old; Address; Adolescence; Adolescent; Affect; Age; Agriculture; Animal Model; Animals; Bioinformatics; Biological; Biological Markers; Birth; Blood; Candidate Disease Gene; Cell model; Child; Child health care; Childhood; Collection; Cosmetics; DNA Methylation; Data; Development; Diet; Disease; Elderly; Endocrine Disruptors; Energy Intake; Energy Metabolism; Enrollment; Environmental Exposure; Epidemic; Epidemiologic Studies; Epigenetic Process; Etiology; Exposure to; Functional RNA; Future; Gene Expression; Genes; Genetic Predisposition to Disease; Goals; Growth; Health; High Prevalence; Hormones; Human; In Vitro; Interdisciplinary Study; Isoprostanes; Latino; Lead; Leptin; Link; Measures; Mediating; Metabolic; Metabolic syndrome; Methodology; Methylation; Mexican Americans; Minority; Modification; Molecular; Mothers; National Health and Nutrition Examination Survey; Not Hispanic or Latino; Obesity; Outcome; Overweight; Oxidative Stress; Participant; Pattern; Perinatal Exposure; Peroxisome Proliferator-Activated Receptors; Physical activity; Plastics; Policies; Population; Pregnancy; Pregnant Women; Prevalence; Proteins; Puberty; Race; Rat Cell Line; Research; Role; Salinum; Sampling; Site; United States; Urine; adipokines; adiponectin; bisulfite; cohort; critical period; early adolescence; early life exposure; environmental chemical; epigenetic marker; genome-wide; high risk; histone modification; improved; in utero; lifestyle factors; lipid biosynthesis; methylome; next generation; obesity in children; obesity risk; obesogen; phthalates; prenatal; prevent; programs; public health relevance; response; sex; social; waist circumference; 14 year old; 9 year old; Address; Adolescence; Adolescent; Affect; Age; Agriculture; Animal Model; Animals; Bioinformatics; Biological; Biological Markers; Birth; Blood; Candidate Disease Gene; Cell model; Child; Child health care; Childhood; Collection; Cosmetics; DNA Methylation; Data; Development; Diet; Disease; Elderly; Endocrine Disruptors; Energy Intake; Energy Metabolism; Enrollment; Environmental Exposure; Epidemic; Epidemiologic Studies; Epigenetic Process; Etiology; Exposure to; Functional RNA; Future; Gene Expression; Genes; Genetic Predisposition to Disease; Goals; Growth; Health; High Prevalence; Hormones; Human; In Vitro; Interdisciplinary Study; Isoprostanes; Latino; Lead; Leptin; Link; Measures; Mediating; Metabolic; Metabolic syndrome; Methodology; Methylation; Mexican Americans; Minority; Modification; Molecular; Mothers; National Health and Nutrition Examination Survey; Not Hispanic or Latino; Obesity; Outcome; Overweight; Oxidative Stress; Participant; Pattern; Perinatal Exposure; Peroxisome Proliferator-Activated Receptors; Physical activity; Plastics; Policies; Population; Pregnancy; Pregnant Women; Prevalence; Proteins; Puberty; Race; Rat Cell Line; Research; Role; Salinum; Sampling; Site; United States; Urine; adipokines; adiponectin; bisulfite; cohort; critical period; early adolescence; early life exposure; environmental chemical; epigenetic marker; genome-wide; high risk; histone modification; improved; in utero; lifestyle factors; lipid biosynthesis; methylome; next generation; obesity in children; obesity risk; obesogen; phthalates; prenatal; prevent; programs; public health relevance; response; sex; social; waist circumference

DESCRIPTION (provided by applicant): In the last 30 years, the prevalence of obesity has risen sharply among children, and minority populations are particularly vulnerable. In the CHAMACOS birth cohort, a Mexican-American population from the agricultural Salinas Valley, CA, children have a particularly high prevalence of obesity (>39% at age 9) compared to both Mexican-American children (25%) and children of all races (20%) in the United States. Changes in diet and physical activity patterns do not completely explain the current obesity epidemic. Recent research suggests that exposure to environmental obesogens, particularly during the prenatal period, may also contribute to increases in obesity. Evidence from animals and epidemiologic studies suggests that phthalates, components of plastics and cosmetics ubiquitously found in humans, may be obesogenic. For instance, as shown in animals, they can change levels of biomarkers of obesity such as adipokines, protein hormones that regulate adipogenesis. There is also growing evidence that environmental exposures can influence DNA methylation (one of the main types of epigenetic markers) and result in adverse health outcomes. However, to date, no data are available on the effects of prenatal phthalate exposure on the molecular mechanisms of obesity in children or the potential role of epigenetic dysregulation. The overall goal of this proposal is to determine whether prenatal phthalate exposure contributes to the development of childhood obesity and metabolic syndrome (MetS) and to examine whether epigenetic changes mediate this relationship. We hypothesize that in utero phthalate exposure alters DNA methylation and leads to changes in adipokines (adiponectin and leptin), oxidative stress (isoprostanes), and higher risk of obesity and metabolic MetS in children. First, we will assess whether early and/or late pregnancy exposures are associated with a) biomarkers (adiponectin, leptin and isoprostane) and b) parameters of obesity and MetS in children at 5, 9 and 14 years of age. Second, we will characterize DNA methylation patterns in children at birth and 9 years of age, and examine whether site-specific changes in the methylome (by 450K array) are associated with a) prenatal phthalate exposure and b) biomarkers and parameters of obesity and MetS. Finally, we will validate 450K array data using next generation bisulfite sequencing and the most advanced expression and bioinformatic methodologies. The proposed research utilizes the rich collection of biological samples and data on exposures, diet, activities, and health outcomes in CHAMACOS participants. By extending assessment of children to age 14, this study will include critical periods of obesity development spanning pregnancy through adolescence. Our results will help elucidate the longitudinal effects of phthalates on obesity, explore the role of epigenetics and adipokines in the development of obesity and MetS, and address important gaps in our understanding of obesity. They will also inform policies aimed at improving children's health and preventing child obesity.

描述（由申请人提供）：在过去的30年中，儿童的肥胖症患病率急剧上升，少数族裔人口特别脆弱。在Chamacos出生队列中，来自加利福尼亚州农业萨利纳斯山谷的墨西哥裔美国人人口，与墨西哥裔美国人儿童（25％）和美国所有种族的儿童（20％）相比，儿童的肥胖症患病率特别高（> 39％）。饮食和体育锻炼模式的变化不能完全解释当前的肥胖流行。最近的研究表明，尤其是在产前期间，可能会导致肥胖症的升高。动物和流行病学研究的证据表明，邻苯二甲酸盐，人类普遍存在的塑料和化妆品的成分可能是肥胖的。例如，如动物所示，它们可以改变肥胖的生物标志物水平，例如脂肪因子，调节脂肪形成的蛋白质激素。越来越多的证据表明，环境暴露会影响DNA甲基化（表观遗传标记的主要类型之一），并导致不良健康结果。但是，迄今为止，尚无有关邻苯二甲酸酯暴露对儿童肥胖分子机制的影响或表观遗传失调的潜在作用。 该提案的总体目标是确定产前邻苯二甲酸盐暴露是否有助于儿童肥胖和代谢综合征（METS）的发展，并检查表观遗传学变化是否介导了这种关系。我们假设在子宫内暴露会改变DNA甲基化，并导致脂肪因子（脂联素和瘦素）的变化，氧化应激（异丙烷）以及儿童肥胖和代谢性MET的较高风险。首先，我们将评估早期和/或晚期妊娠暴露与a）生物标志物（脂联素，瘦素和异丙烷）和b）5、9和14岁儿童的肥胖和大都会的参数有关。其次，我们将表征出生时儿童和9岁儿童中的DNA甲基化模式，并检查甲基甲基组的位点特异性变化是否与a）邻苯二甲酸盐暴露和b）邻苯二甲酸酯和b）肥胖和Mets的生物标记物以及b）。最后，我们将使用Next Generation Bisulfite测序以及最先进的表达和生物信息学方法来验证450K阵列数据。 拟议的研究利用了Chamacos参与者中有关暴露，饮食，活动和健康成果的丰富收集生物样品和数据。通过将儿童的评估扩展到14岁，这项研究将包括肥胖的关键时期，这些肥胖症跨越了妊娠到青春期。我们的结果将有助于阐明邻苯二甲酸酯对肥胖症的纵向影响，探索表观遗传学和脂肪因子在肥胖和大都会的发展中的作用，并解决我们对肥胖症的理解中的重要差距。他们还将为旨在改善儿童健康和预防儿童肥胖的政策提供信息。